Summary Exosomes are emerging to play an important role in immune surveillance and neuronal survival of the central nervous system (CNS), as they mediate the intercellular communications between neurons and other brain cells, including astrocytes and neurovascular endothelial cells. However, the role of exosomes in HIV-mediated neuroinvasion is largely unknown. We recently identified that exosomes isolated from the plasma of HIV-infected subjects contain significantly high levels of microRNA-17 (miR- 17) and miR-20a that can target tight junction proteins ZO-1 and JAM-2. A further pilot study using cell culture-derived exosomes showed that exosomes from HIV-infected macrophages breached blood-brain barrier (BBB) integrity. Thus, we hypothesize that exosomes derived from plasma of HIV-infected subjects contain miRNAs that impair BBB functions, facilitating organotropic viral dissemination to the brain and resulting in neurodegeneration. We propose two specific aims to address this hypothesis: Aim 1. To investigate the effect of plasma exosomes from HIV-infected subjects or uninfected controls on BBB functions and identify the role of miR-17 and miR-20a in this process. Aim 2. To profile and compare the miRNA spectra of exosomes from the plasma and cerebrospinal fluid of HIV- infected subjects with or without neurocognitive disorders. The functional significance of the exosomes and the differentially expressed exosomal miRNAs will be validated on neuronal survival, astroglial differentiation and BBB functions. This project, with both in vitro and in vivo studies, should provide novel pathogenetic insights into HIV infection of the CNS.